Dia Care-2015-Fox-1777-803

Diabetes Care Volume 38, September 2015Update on Prevention of Cardiovascular Disease in Adults With Type 2 Diabetes Mellitus in Light of Recent Evidence: A Scientific Statement From the American Heart Association and the American Diabetes Association Cardiovascular disease risk factor control as primary prevention in patients with type 2 diabetes mellitus has changed substantially in the past few years. The purpose of this scientific statement is to review the current literature and key clinical trials pertaining to blood pressure and blood glucose control, cholesterol management, aspirin therapy, and lifestyle modification. We present a synthesis of the recent literature, new guidelines, and clinical targets, including screening for kidney and subclinical cardiovascular disease for the contemporary management of patients with type 2 diabetes mellitus. Diabetes mellitus, defined by elevated glycemic markers, is a major risk factor for cardiovascular disease (CVD), which is the most common cause of death among adults with diabetes mellitus (1), underscoring the need for aggressive CVD risk factor management. In 1999, the American Heart Association (AHA) and the American Diabetes Association (ADA) published a joint statement focused on CVD prevention in diabetes mellitus (2). In 2007, the AHA and ADA again issued a combined set of recommendations focused on the primary prevention of CVD in diabetes mellitus (3). Since then, several new clinical trials have emerged that have changed the clinical practice of CVD risk management in diabetes mellitus. Since the earlier scientific statement, diabetes mellitus screening and diagnosis have changed, with the inclusion of glycated hemoglobin (A1c) of at least 6.5% in the diagnostic criteria of type 2 diabetes mellitus (4). This change in criteria has identified separate subsets of newly diagnosed patients with diabetes mellitus while the overall diabetes mellitus epidemic continues, with a 75% increase in the number of affected individuals with diabetes mellitus across all age-groups from 1988 to 2010 (5). Fewer than half of U.S. adults meet recommended guidelines for diabetes mellitus care (6), underscoring the magnitude of the public health burden of type 2 diabetes mellitus. Given the changes in the diabetes mellitus landscape over the past 5 years, the purpose of this scientific statement is to summarize key clinical trials pertaining to lifestyle, blood glucose, blood pressure, and cholesterol management for the primary prevention of CVD. We have synthesized the established clinical guidelines and Caroline S. Fox, Co-Chair; Sherita Hill Golden, Co-Chair; Cheryl Anderson; George A. Bray; Lora E. Burke; Ian H. de Boer; Prakash Deedwania; Robert H. Eckel; Abby G. Ershow; Judith Fradkin; Silvio E. Inzucchi; Mikhail Kosiborod; Robert G. Nelson; Mahesh J. Patel; Michael Pignone; Laurie Quinn; Philip R. Schauer; Elizabeth Selvin; and Dorothea K. Vafiadis; on behalf of the American Heart Association Diabetes Committee of the Council on Lifestyle and Cardiometabolic Health, Council on Clinical Cardiology, Council on Cardiovascular and Stroke Nursing, Council on Cardiovascular Surgery and Anesthesia, Council on Quality of Care and Outcomes Research, and the American Diabetes Association The input provided by Drs. Fox, Ershow, Nelson, and Fradkin is from their own perspective, and the opinions expressed in this article do not reflect the view of the National Institutes of Health, Department of Health and Human Services, or the U.S. government. Dr. Pignone is a member of the U.S. Preventive Services Task Force. His contributions here represent his views alone and not necessarily those of the U.S. Preventive Services Task Force. The American Diabetes Association and the American Heart Association make every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest. Corresponding author: Caroline S. Fox, foxca@ nhlbi.nih.gov. This document was approved by the American Diabetes Association on 7 January 2015 and the American Heart Association Science Advisory and Coordinating Committee on 30 April 2015 and the American Heart Association Executive Committee on 22 May 2015. This article has been copublished in Circulation. © 2015 by the American Diabetes Association and the American Heart Association, Inc. SCIENTIFIC STATEMENT Diabetes Care 2015;38:1777–1803 | DOI: 10.2337/dci15-0012 1777 1778 Scientific Statement clinical targets for the contemporary management of patients with type 2 diabetes mellitus to reduce CVD risk. When possible, we have included the AHA/ American College of Cardiology (ACC) Class of Recommendation/Level of Evidence grading system (Table 1) or the ADA evidence grading system for clinical practice recommendations (Table 2) (4). Specifically, we start with the updated diagnostic criteria for diabetes mellitus. Next, we focus on lifestyle management in diabetes mellitus, including physical Diabetes Care Volume 38, September 2015 activity and nutrition. Then, we focus on CVD risk factor management in diabetes mellitus, including weight management, aspirin use, glucose control, blood pressure management, and lipid management. Next, we move to screening for renal and CVD complications of diabetes mellitus. Finally, we close with a list of selected areas of controversy requiring further research. Throughout, we emphasize that this document is not a comprehensive review of the literature but rather a focus on the major new trials that have led to recent guideline changes in the area of primary prevention of CVD in type 2 diabetes mellitus. NEW DIAGNOSTIC CRITERIA FOR DIABETES MELLITUS AND PREDIABETES In 2010, the ADA included A1c for the first time among the tests recommended for the diagnosis of diabetes mellitus. This recommendation has also been adopted by the European Association for the Study of Diabetes, the World Health Table 1—Applying classification of recommendations and Level of Evidence A recommendation with Level of Evidence B or C does not imply that the recommendation is weak. Many important clinical questions addressed in the guidelines do not lend themselves to clinical trials. Although randomized trials are unavailable, there may be a very clear clinical consensus that a particular test or therapy is useful or effective. *Data available from clinical trials or registries about the usefulness/efficacy in different subpopulations, such as sex, age, history of diabetes, history of prior myocardial infarction, history of heart failure, and prior aspirin use. †For comparative effectiveness recommendations (Class I and IIa; Level of Evidence A and B only), studies that support the use of comparator verbs should involve direct comparisons of the treatments or strategies being evaluated. Recent studies have also established robust relationships of A1c with future risk of diabetes mellitus. however. is also associated with cardiovascular outcomes after adjustment for traditional cardiovascular risk factors (19.7% to 6.0% to 5.7% and 6. and other professional groups in the U.7% to 6.care. Elevated A1c. greatly enhancing the power to detect a modest association. mg/dL $6. with no obvious threshold. Randomized. Strengths and Limitations of Using A1c for Diabetes Mellitus Diagnosis There are a number of advantages of using A1c for diagnosing diabetes mellitus. Evidence for current diagnostic cut points also includes epidemiological studies demonstrating strong.24).g.S. “all or none” rule developed by the Centre for Evidence-Based Medicine at the University of Oxford) Supportive evidence from well-conducted RCTs that are adequately powered.4% are classified as having an increased risk for diabetes mellitus (Table 3) (4). an analysis of data from a large Japanese population showed that individuals with an A1c of $6. along with fasting glucose of 100 to 125 mg/dL or 2-h glucose of 140 to 199 mg/dL.50 separate epidemiological cohorts. including the following: c Evidence from a well-conducted trial at one or more institutions c Evidence from a meta-analysis that incorporated quality ratings into the analysis B Supportive evidence from well-conducted cohort studies c Evidence from a well-conducted prospective.7–6. The high risk of both diabetes mellitus and CVD among people with an A1c of 5. A1c and Prediabetes Epidemiological studies have shown that individuals with A1c in the range of 5.7% to 6. the ADA also added A1c to the tests used to identify people with prediabetes. cross-sectional associations for fasting glucose. and all-cause mortality in initially nondiabetic populations (17–20). Copyright © 2015.20. there are also some limitations to consider (18. graded. There is a strong risk gradient between 5.26. including the following: c Evidence from a well-conducted multicenter trial c Evidence from a meta-analysis that incorporated quality ratings into the analysis Compelling nonexperimental evidence (i. Some A1c measurement methods are known to give falsely high or low values 1779 . even below the threshold for diagnosis of diabetes mellitus. case series with comparison with historical control subjects) c Evidence from case series or case reports Conflicting evidence with the weight of evidence supporting the recommendation E Expert consensus or clinical experience Organization. individuals with A1c in the range of 5. generalizable RCTs that are adequately powered.29–33) that are summarized in Table 4. supporting the use of this range to define prediabetes. mg/dL $200 N/A Modified from “Standards of Medical Care in Diabetesd2015” (4). These data linking A1c to both microvascular and macrovascular outcomes provide further evidence to support the new A1c criteria.5% had an elevated risk of newly developed retinopathy during 3 years of follow-up compared with those with A1c values in the range of 5.23. Thus. 2-h glucose. in a recent very large study that pooled data from . mg/dL $200 140–199 Random glucose in patients with classic symptoms of diabetes mellitus..5% or previous criteria for fasting glucose ($126 mg/dL) or 2-h glucose ($200 mg/dL) can be used for the diagnosis of diabetes mellitus (Table 3) (4). fasting glucose levels in the nondiabetes range were moderately but significantly associated with risk of vascular death (28). However. American Diabetes Association. CVD. the A1c threshold for increased diabetes mellitus risk is less clearly defined than that for a diagnosis of diabetes mellitus.diabetesjournals.4% highlights the need for cardiovascular and diabetes mellitus prevention efforts in this population. In one of the few prospective studies of retinopathy. Clinical practice recommendations from the ADA now state that an A1c value of $6. and A1c with Table 3—Diagnostic criteria for diabetes mellitus and categories of increased risk for diabetes mellitus and prediabetes Diabetes mellitus Prediabetes A1c.4%. chronic kidney disease (CKD). who are at increased risk for type 2 diabetes mellitus.27). The evidence for an association of impaired fasting glucose (100–125 mg/dL) with cardiovascular outcomes is less robust (25).20. prevalent retinopathy (11–15). Indeed. possibly because of the higher variability in fasting glucose levels compared with A1c (26.org Fox and Associates Table 2—ADA evidence grading system for clinical practice recommendations (4) Level of Evidence A Description Clear evidence from well-conducted..e.5 $126 5.4% have a high risk of future diabetes mellitus (20–22).4% (16). % Fasting glucose.4 100–125 2-h glucose. In 2010. clinical trials have demonstrated that improvements in glycemic control reduce the risk of microvascular complications (8–11). A1c and Diabetes Mellitus A major strength of using A1c for the diagnosis of diabetes mellitus is the evidence linking A1c to clinical outcomes. cohort study or registry c Evidence from a well-conducted meta-analysis of cohort studies Supportive evidence from a well-conducted case-control study C Supportive evidence from poorly controlled or uncontrolled studies c Evidence from randomized clinical trials with one or more major or three or more minor methodological flaws that could invalidate the results c Evidence from observational studies with a high potential for bias (e. using the stairs instead of elevators. blood pressure. In summary. provided extensive longitudinal data on the effect of an intensive lifestyle intervention.34%. increasing to $175 Certain conditions interfere with the interpretation of results (18.0% versus 3.51).1780 Scientific Statement Diabetes Care Volume 38. lifestyle management is a cornerstone of clinical care. had greater reductions in A1c and waist circumference. which was attenuated but still sustained by the end of the study (6. conducted from 2001 to 2012. although modern assays are mostly unaffected by common variants (29). controlled trial (RCT) of 262 sedentary patients with diabetes mellitus randomized to the nonexercise control group or to a resistance training alone.29.7 6 110. so individuals with prediabetes can be targeted for diabetes mellitus risk reduction and patients with diabetes mellitus can receive aggressive cardiovascular risk prevention. current guidelines represent a convenient approach to identifying individuals with either condition. A recent randomized. and some other countries (33) More robust predictor of complications than fasting blood glucose (18.. Nutrition In addition to physical activity.31. red cell turnover. particularly statins. In this trial. Current nutrition recommendations for individuals with type 2 diabetes mellitus center around a dietary pattern that emphasizes intake of fruits. Eating patterns such as the Dietary Approaches to Stop Hypertension (DASH).4 min/week of physical activity.S. Because the same tests identify diabetes mellitus and prediabetes. However. and education as a cornerstone of optimal diabetes mellitus treatment (4. and lipid control.95 [95% CI 0.7%).33) (www. The second component of the physical activity intervention included a focus on lifestyle activity (e. At a minimum. Mediterranean. ´ con Dieta Mediterr´anea The Prevencion (PREDIMED) trial was an RCT looking at . loss of blood) Lack of assay standardization in many parts of the world Cost and lack of availability in resource-poor areas min/week of moderately intense activity by week 26 (34). nutrition plays an important role in the treatment of type 2 diabetes mellitus and CVD risk prevention. that is.ngsp. in the intervention group resulting from an improvement in risk factors with the lifestyle intervention. P 5 0. on CVD rates (the primary outcome) and CVD risk factors among adults with type 2 diabetes mellitus. However. physical activity) (30) Already used as a guide to adjust diabetes mellitus treatment (33) Laboratory methods are well standardized in the U. providing global index of glycemic exposure (tracks well over time) Less biological (day-to-day) variability compared with single fasting or 2-h glucose (26. exercise. after a median follow-up of 9. an aerobic training alone. The primary results of Look AHEAD were published in 2013 (37). reduced saturated fat. pregnancy.6%) compared with the usual care arm (0. and required less medication for glucose.03) (39). The reasons for this are not clear (38) but may be the result of decreased use of cardioprotective drugs. and low-fat dairy products. or monitored carbohydrate diet are effective for controlling glycemia and lowering CVD risk factors (44). or a combined resistance and aerobic training group showed that only the combined exercise was associated with lower A1c levels (mean decline 0. moreover.20) in the presence of hemoglobin variants. Published recommendations for the treatment of people with diabetes mellitus assert the continued importance of diet.09]. recent transfusion. low-fat.40–43). greater weight loss was observed in the intervention arm (8. other nonglycemic determinants of A1c.32) Eliminates need for fasting or timed samples Unaffected by acute illness or recent activity (e. At 1 year. Participants were provided a pedometer in the seventh week and instructed to increase their daily steps by 250 each week until they reached the goal of $10.575 participants were randomized to a control group and 2.000 a day.570 to an intervention that consisted of a weekly goal for physical activity of 50 min/week initially.. LIFESTYLE MANAGEMENT OF TYPE 2 DIABETES MELLITUS Once type 2 diabetes mellitus is diagnosed. targeting weight reduction through caloric restriction and increased physical activity.org). One-year results revealed that participants in the intensive lifestyle intervention achieved an average of 136. P 5 0. The recommendations also consist of individualized modification of macronutrient intake to accommodate individual needs for the distribution of calories and carbohydrates over the course of the day. This section reviews some of the evidence from large clinical trials that focus on lifestyle management in type 2 diabetes mellitus. These findings highlight how exercise type may be as important as exercise quantity in type 2 diabetes mellitus. vegetables.5%). hemolytic anemia. hemoglobin characteristics (other than hemoglobinopathies). there was a significant association between the minutes of physical activity and weight loss at 12 months (36).. which is equally as effective as aerobic activity in leading to weight loss and improvement in CVD risk factors (35). In addition to absolute amounts of exercise. updated diagnostic criteria for diabetes mellitus are well aligned with the current evidence linking A1c to longterm complications.6 years.g.g. 2. the trial was stopped early because of futility: There were 403 CVD events in the intervention arm compared with 418 CVD events in the usual care arm (hazard ratio [HR] 0. walking instead of riding). the study informs clinicians that increased physical activity and improvements in diet can safely lead to weight loss and reduced requirement for medication to control CVD risk factors without a concomitant increase in the risk of cardiovascular events.g. the patients in the intervention arm had improved physical fitness and HDL cholesterol (HDL-C) levels. including hemoglobin traits and alterations in red cell turnover (e. September 2015 Table 4—Strengths and limitations of using A1c for diabetes mellitus diagnosis Strengths Limitations Reflects chronic hyperglycemia. may contribute to variability in the population (30). Physical Activity The Look AHEAD (Action for Health in Diabetes) study. the type of exercise in patients with diabetes mellitus might make a difference. and the tendency of hemoglobin to undergo glycation. In addition to weight loss.83–1. Pharmacological therapy should include a regimen with either an ACEI or an ARB (ADA Level of Evidence B). limited life expectancy. this can be achieved with a mean plasma glucose of 8.2. legumes.5%) might be considered in selected patients (with short disease duration. Individualized medical nutrition therapy for all patients with diabetes mellitus (ADA Level of Evidence A). achieve a goal of .10 mmol/L (.130 mg/dL) and postprandial glucose at .2 mmol/L (.140 mmHg (ADA Level of Evidence A) but that lower systolic targets (e. the other should be substituted (ADA Level of Evidence C) (4). Grade E).. and dairy products in place of other carbohydrate sources (ADA Level of Evidence B). More stringent A1c targets (e. antihypertension treatment should include an ACEI or ARB (Expert Opinion.care.g.3–8.130 mmHg) may be appropriate for certain individuals such as younger patients if it can be achieved without undue treatment burden (ADA Level of Evidence C) (4). repeated counseling. Level of Evidence A).0% in most patients to reduce the incidence of microvascular disease (ADA Level of Evidence B).. Less stringent A1c goals (e. cognitive impairment. For patients with CKD.500 mg/day). similar to recommendations for the general population (ADA Level of Evidence B. . fasting and premeal glucose should be maintained at .8.org Fox and Associates Table 5—Current recommendations for CVD risk factor management in type 2 diabetes mellitus Risk factor Relevant statement or guideline Specific recommendation and Level of Evidence Nutrition “Nutrition Therapy Recommendations for the Management of Adults With Diabetes” (43) Reduction of energy intake for overweight or obese patients (ADA Level of Evidence A). Carbohydrate monitoring as an important strategy for glycemic control (ADA Level of Evidence B). advanced complications. Hypertension/blood pressure control has been revised to suggest that the systolic blood pressure goal for many people with diabetes mellitus and hypertension should be . long life expectancy.diabetesjournals.g. Grade E) (60. and extensive comorbid conditions and those in whom the target is difficult to attain despite intensive self-management education. Obesity “2013 AHA/ACC/TOS Guideline for the Management of Overweight and Obesity in Adults: A Report of the American College of Cardiolgy/American Heart Association Task Force on Practice Guidelines and The Obesity Society” (58) Overweight and obese patients should be counseled that lifestyle changes can produce a 3%–5% rate of weight loss that can be sustained over time and that this can be associated with clinically meaningful health benefits (ACC/AHA Class I. . Continued on p. lower targets may be appropriate for some individuals.7. although the guidelines have not yet been formally updated to incorporate this new information (Expert Opinion. Mediterranean-style dietary pattern may improve glycemic control and CVD risk factors (ADA Level of Evidence B). whole grains.140/90 mmHg.300 mg/day. no significant CVD) if this can be achieved without significant hypoglycemia or other adverse effects of treatment (ADA Level of Evidence C). Limit of sodium to .180 mg/dL). the American College of Cardiology. if one class is not tolerated. bariatric surgery may improve health (ACC/AHA Class IIa.g.0% or even slightly higher) are appropriate for patients with a history of severe hypoglycemia. Blood glucose “Management of Hyperglycemia in Type 2 Diabetes: A Patient-Centered Approach: Position Statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)” (59) “Standards of Medical Care in Diabetesd2015” (4) Lower A1c to #7. .9 mmol/L (150–160 mg/dL). and the Centers for Disease Control and Prevention” (60) “2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults: Report From the Panel Members Appointed to the Eighth Joint National Committee (JNC 8)” (61) “Standards of Medical Care in Diabetesd2015” (4) For most individuals with diabetes mellitus. Blood pressure “An Effective Approach to High Blood Pressure Control: A Science Advisory From the American Heart Association. and effective doses of multiple glucoselowering agents.6.. note that the AHA differs and recommends sodium . Level of Evidence A). Consumption of fruits. For patients with BMI $40 kg/m2 or BMI $35 kg/m2 with an obesity-related comorbidity who want to lose weight but have not responded to behavioral treatment with or without pharmacological treatment. 1782 1781 . vegetables. including insulin (ADA Level of Evidence B). ideally.61).1. 114 kg and 1..g. polyunsaturated fatty acids) for saturated and trans fats. in subsequent years. Those patients randomized to the Mediterranean diet had a 30% reduced risk of CVD events (45). Evaluate and treat patients with fasting triglycerides . The final component of the lifestyle program was the use of a toolbox. There is extensive empirical evidence on the association between self-monitoring and successful outcomes in weight loss treatment (68. substituting healthy fats (e. to prevent or delay diabetes mellitus complications.75 years of age. including consideration of potential risks.. Of all the behavioral strategies taught in these sessions. Nutritional Recommendations The ADA recently issued a position statement on nutritional recommendations for adults living with diabetes mellitus (43). Statin therapy of high intensity‡ should be given to individuals with diabetes mellitus between 40 and 75 years of age with a $7. Whether vitamin D supplementation will ultimately be important in preventing diabetes mellitus remains to be determined. self-monitoring or recording one’s food intake and physical activity was likely the most important strategy for success. angiotensin receptor blocker. The Obesity Society.40 or . In type 2 diabetes mellitus. they were also encouraged to weigh themselves more often because there is evidence that more frequent weighing is associated with improved weight loss and maintenance (70. engaging in regular physical activity.67). Numerous clinical trials have established the efficacy of this approach (64. and to provide those living with diabetes mellitus tools for meal planning. B vitamins.71).500 to 1. Level of Evidence B). a landmark trial is the recent Look AHEAD study. The stated goals of nutrition therapy for adults with diabetes mellitus are to attain individualized glycemic. Key specific recommendations (43) can be found in Table 5.50%. Lifestyle The primary approach to weight management is lifestyle. and behavior changes related to lifestyle. The physical activity component is described in detail in the previous section. ACEI. randomized trials in individuals with diabetes mellitus (53.30% of total calories and .500 kcal/day for those weighing . and losing excess weight. The importance of the glycemic index needs further investigation.54). increased energy expenditure through increased daily physical activity and regular aerobic activity 3 to 5 days/week. practitioners should evaluate the benefit of statin treatment (ACC/AHA Class IIa. limiting added sugars.e. The third component was focused on behavior modification and included group sessions during the first year. which includes three components: dietary change that is focused on caloric restriction. and surgical approaches in type 2 diabetes mellitus. ‡High-intensity statin lowers LDL-C on average by . The prespecified diabetes mellitus subgroup demonstrated similar results. TOS. drug interactions. a . Level of Evidence C). However. it is important to optimize nutrition-related practices.10% from saturated fat. *Moderate-intensity statin therapy lowers LDL-C on average by 30% to 50%. and adverse events.800 for those weighing $114 kg. ARB. whereas other studies have shown no effect of low–glycemic index diets on triglycerides (49–51).200 to 1. the effect of a Mediterranean diet on CVD outcomes. omega-3 fatty acids) (54–57). lipid. Among individuals with diabetes mellitus who are . and blood pressure goals. Given that individuals with diabetes mellitus commonly have elevated triglycerides and reduced HDL-C levels. atherosclerotic cardiovascular disease. WEIGHT MANAGEMENT The next section of this update focuses on weight management through lifestyle. Additional goals included restricting fat to . benefits. there are no conclusive studies in patients with diabetes mellitus. including moderate alcohol intake. Dietary Supplements With regard to dietary supplements. In terms of the specific intervention. to achieve and maintain healthy body weight. These changes can reduce triglycerides by 20% to 50% (52). monounsaturated fatty acids. Individuals were weighed before each session and were provided feedback. the Look AHEAD trial intensive intervention diverged from that of the Diabetes Prevention Program (DPP) in that there were more counseling sessions extending over a longer duration with both individual and group treatment in addition to the meal replacements that were provided (34).500 mg/dL. ASCVD. or specific fatty acids (e. pharmacological. In individuals without diabetes mellitus. Some data suggest that eating patterns with low glycemic index may be effective in achieving glycemic control (i. no consistent findings have emerged from large-scale.g. angiotensin-converting enzyme inhibitor.5% estimated risk of ASCVD (ACC/ AHA Class IIa. suggesting that a Mediterranean diet may promote CVD risk reduction in patients with diabetes mellitus.1782 Scientific Statement Diabetes Care Volume 38. †We note that these recommendations do not replace clinical judgment.65). September 2015 Table 5—Continued Risk factor Cholesterol Relevant statement or guideline “2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines” (62) “Standards of Medical Care in Diabetesd2015” (4) Specific recommendation and Level of Evidence Patients with diabetes mellitus between 40 and 75 years of age with LDL-C between 70 and 189 mg/dL should be treated with a moderate-intensity statin*† (ACC/AHA Class I. positive effects on postprandial blood glucose and insulin) and in lowering triglyceride levels (46–48). The dietary component of the trial included an energy goal of 1.. Meal replacements are an approach that addresses portion control and the difficulty individuals have in estimating calorie content of consumed foods (66.69). some studies have demonstrated an association with lower CVD risk when a healthful diet is supplemented with antioxidant vitamins. contact was achieved by monthly individual sessions and by telephone. Level of Evidence A) (ADA Level of Evidence A). Food and Drug Administration. although they contain no specific recommendation for the use of medications.1% in the usual care group. 1959 Benzphetamine. and leisure time.S. despite a mean weight increase of 3. and 15% protein) designed to obtain a negative balance of 500 kcal/day against energy expended. and coronary heart disease (CHD) risk scores (74). 2012 Qsymia 3. In clinical trials. with weight gain deserves specific mention. The purpose of the toolbox was to have an array of strategies to use with an individual who was not achieving adequate adherence to the protocol or who had lost . U. At 4 years. year of approval Trade name(s) Dose DEA schedule Xenical Alli (over the counter) 120 mg 3 times daily before meals 60 mg 3 times daily before meals Not scheduled Not scheduled Serotinin-2C receptor agonist approved by the FDA for long-term use (12 months) Lorcaserin. Consistent with the DPP findings.org strategy also used in the DPP. 1959 Phentermine. pharmacological therapy is indicated for individuals with a BMI of 25 to 30 kg/m2 with comorbidities or a BMI . However. campaigns. Compared with the control group. A1c. waist circumference. and diabetes mellitus treatment to 150 min of twice-a-week supervised aerobic and resistance training plus structured exercise counseling (exercise group) or to structured individualized counseling alone (control group) for 12 months. 1783 . which occurred every 3 months.5–70 mg 3 times daily 105 mg daily IV Pancreatic lipase inhibitor approved by the FDA for longterm use ($12 months) Orlistat.5/46 mg 15/92 mg IV Tenuate Tenuate Dospan Adipex and many others Didrex Bontril Prelu-2 25 mg 3 times a day 75 mg every morning 15–30 mg/day 25–50 mg 3 times daily 17. further work in type 2 diabetes mellitus is needed to elucidate the role of physical activity and weight loss in reducing clinical CVD end points (37). FDA. despite weight loss and concomitant improvement in CVD risk factors. *Side effect profiles can be found in the package inserts for each agent. 30% fat. participants in the intensive lifestyle arm of Look AHEAD lost 4. older individuals had greater adherence to session attendance. The subjects were randomized by center. inflammation. participants were encouraged to meet the current physical activity recommendations through increasing energy expenditure during commuting. including medications or surgery. age. Table 6—Drugs approved by the FDA for weight loss* Generic name. greater participation in the intervention. The association of smoking cessation. The new guidelines for obesity are briefly summarized in Table 5. Fox and Associates Another study examining the role of intensive lifestyle management on CVD risk factors was the Italian Diabetes and Exercise Study (IDES). A previously unanswered question was whether the weight gain of 3 kg to 6 kg that occurs after smoking cessation would be associated with an increased cardiovascular risk in those with diabetes mellitus. In the structured individualized counseling sessions.30 kg/m2 with or without comorbidities. HDL-C and LDL cholesterol (LDL-C) levels. occupational. which. smoking cessation was still associated with a decreased risk of CHD (75). Pharmacological Therapy When lifestyle interventions for weight loss fail to achieve the desired goals. did not demonstrate reduced CVD events in the intensive lifestyle arm. Treatment options included the use of motivational interviewing strategies to assist an individual in goal setting and improved adherence to written contracts with the lifestyle counselor. BMI. A recent observational study found that. supervised exercise produced significant improvements in physical fitness.7% of initial weight compared with 1. insulin resistance. Thus. Drug Enforcement Administration. U. systolic and diastolic blood pressures. 2012 Belviq 10 mg twice daily IV Combination of phentermine-topiramate approved by the FDA for long-term use (12 months) Phentermine-topiramate.S. In accordance with the new AHA/ACC/ The Obesity Society guidelines for weight loss (58). Other techniques used over the subsequent years to keep participants engaged and motivated and to promote weight loss maintenance included refresher courses. Subjects in both groups received dietary counseling. the physician and patient may wish to consider alternatives.12 weeks) Diethylpropion. and incentives such as prizes for campaign winners (72). reviewed above.care. 1999 Orlistat. 1959 IV III III DEA.6 kg for recent (.diabetesjournals. an important CVD prevention strategy. medications and surgery almost always produce more weight loss than the lifestyle/placebo interventions against which they are compared. The IDES was an RCT designed to examine the effects of an intensive exercise intervention strategy on modifiable CVD risk factors in 606 sedentary subjects with type 2 diabetes mellitus enrolled in 22 outpatient diabetes mellitus clinics across Italy (73).75/23 mg 7. home.4 years) quitters. which included caloric intake (55% complex carbohydrates. it is important to reflect on the primary results of Look AHEAD. 1960 Phendimetrazine.1% of baseline weight. 2007 Noradrenergic drugs approved for short-term use (usually . and lower self-reported energy intake and lost more weight than their younger counterparts. including cost. Exenatide and liraglutide are both glucagon-like peptide-1 agonists and produce modest Diabetes Care Volume 38. lorcaserin (82). insulin. At 15 years.30 kg/m2) with type 2 diabetes mellitus who had not achieved the International Diabetes Federation treatment targets with an optimal medical regimen. some that increase weight and others reduce weight. and CVD Outcomes Observational Data. For example.5 years) weight loss outcomes after . Effect of Surgery on Glycemic Control. All agents except orlistat are classified by the U. Many overweight and obese patients also have type 2 diabetes mellitus.5) for those who had gastric bypass. September 2015 weight loss of 5% at doses recommended for the treatment of diabetes mellitus. In clinical trials. This group recommended considering surgery for obese individuals (BMI . However.9) for patients with biliopancreatic diversion or duodenal switch (91). The new AHA/ACC/The Obesity Society guidelines recommend that adults with BMI $35 kg/m2 and an obesity-related comorbidity such as diabetes mellitus who are motivated to lose weight should be considered for referral to a bariatric surgeon (58). A meta-analysis (136 studies) of mostly short-term (. orlistat (81). thiazolidinediones. leading to some degree of malabsorption (bypass procedures). Commonly performed procedures (frequency of use) include the Roux-en-Y gastric bypass (49%). liraglutide. Bupropion/ naltrexone is currently under review while a cardiovascular outcome trial is being conducted (84).80). In addition.12 weeks) and three. diethylpropion.90% follow-up rate) evaluating the long-term effects of bariatric surgery compared with nonsurgical weight management of severely obese patients in a community setting (92). CVD Risk Factors.3–73. pramlintide.2) for patients who underwent gastric banding.6% (95% CI 56. Surgical Procedures for Severe Obesity and Metabolic Disease Bariatric surgery (i. for longer-term use (83). The best long-term surgical weight loss data come from the Swedish Obese Subjects (SOS) study. sustained improvements in glycemia in type 2 diabetes mellitus among patients . Second. a higher dose of liraglutide is being investigated as a long-term treatment for obesity (87). glinides. The sodium–glucose cotransporter-2 inhibitors block the sodium–glucose cotransporter in the renal tubule and can produce modest weight loss. benzphetamine. sleeve gastrectomy (30%).e. the patient should receive effective lifestyle support for weight loss along with the pharmacological agent. Food and Drug Administration for treatment of the patient with obesity (Table 6) (76.5% (95% CI 40. weight loss (percent of total body weight) was 27 6 12% for gastric bypass. the patient should be familiarized with the drugs and their potential side effects. antidepressants. especially if other cardiovascular risk factors were present (90). Several guiding principles should be followed when weight loss agents are prescribed. In general. exenatide. and 70. several for short-term use (usually considered . and biliopancreatic diversion (2%).8) for patients with gastroplasty. Metabolic procedures have evolved since the abandoned jejunoileal bypass of the early 1950s and 1960s. Several drugs are approved by the U. and antiepileptics (76–78). the health care provider should consider changing to the drugs that produce weight loss (78).79. or combining both concepts. and sulfonylureas produce weight gain. although long-term safety data are not yet available (88). because response to medications is variable. The first step in evaluating medications for the obese patient is to make sure that the patient is not taking drugs that produce weight gain. These potentially include certain antidiabetes drugs. there are many selection factors to consider in the choice of glucoselowering agents for patients with diabetes mellitus.4). Drug Enforcement Administration as having the potential for abuse and are schedule III or IV drugs.22. and if they have not lost 5% of their body weight after 3 months of treatment. and 13 6 14% for gastric banding compared with a slight weight gain for control subjects. and phendimetrazine) are approved for short-term use.2% (95% CI 58.1784 Scientific Statement The weight loss achieved with an intensive lifestyle intervention usually wanes over time. four pharmacological agents (phentermine. the term metabolic surgery is rapidly replacing bariatric surgery.S.86). If all other things are equal. the health care provider may wish to use antidiabetes drugs that produce weight loss.1–64. If such agents are identified and if there are acceptable alternatives that are weight neutral or produce weight loss. First. a prospective study (. patients should be re-evaluated regularly.5–74. Third.000 bariatric procedures demonstrated an overall mean excess weight loss (defined as follows: initial body weight in kilograms minus current weight in kilograms divided by initial body weight in kilograms minus ideal body weight times 100%) of 61.7–66.7–54. long-term medical (nonsurgical) weight loss rarely exceeded 8% (37). metabolic operations alter the gastrointestinal tract by reducing stomach capacity (gastric restrictive operations). The development of laparoscopic approaches to all these metabolic procedures in the mid1990s was a major advance resulting in a significant reduction in perioperative morbidity and mortality. and sodium–glucose cotransporter-2 inhibitors produce weight loss (76). Because metabolic and weight-related comorbidities are often improved or resolved through weight loss or neuroendocrine mechanisms.1% (95% CI 66.2% (95% CI 61. In contrast.S. 68. 18 6 11% for verticalbanded gastroplasty. Effect of Surgery on Weight Loss The primary intent of bariatric procedures is a reduction of excess body fat and comorbidity improvement or resolution. and metformin. and extended-releasetopiramate/phentermine. dipeptidyl peptidase-4 inhibitors are weight neutral. Multiple observa- tional studies demonstrate significant. The indications for weight loss surgery have evolved since the seminal National Institutes of Health guidelines from 1991. adjustable gastric banding (19%). weight loss surgery) is the most effective treatment for attaining significant and durable weight loss in severely obese patients. rerouting nutrient flow.. which recommended surgical intervention for weight loss in patients with a BMI $40 kg/m2 or a BMI $35 kg/m2 with significant obesity-related comorbidities (89). a new plan should be implemented (85. and there are several hypoglycemic therapies to choose from (76). 61. 47. The most recent guidelines for bariatric surgery pertaining to patients with type 2 diabetes mellitus came from the International Diabetes Federation in 2011. 8 months. fasting blood glucose. studies have evaluated the effect of metabolic surgery on the progression of microvascular disease such as retinopathy. The most common complications are summarized in Table 7 (105). Bariatric surgery was also markedly more effective than nonsurgical treatment in the prevention of type 2 diabetes mellitus. adjustable gastric banding. 0..543 patients (93). The longer-term durability of these findings remains unknown.care.98). Complications of Surgery. Four short-term (1–2 years) RCTs have compared bariatric surgery with medical treatment of type 2 diabetes mellitus. as well as whether improvements in CVD risk factors will ultimately translate into CVD event reduction.47 [95% CI 0. RYGB. 0.931) and total mortality from 30 days to 2 years of 0. Immediate. E. A meta-analysis of published mortality data after bariatric surgery reported an overall 30-day postoperative mortality of 0.34 Late complications for AGB Band slippage Leakage Erosion Late complications of bypass procedures Anastomotic strictures Marginal ulcers Bowel obstructions Micronutrient and macronutrient deficiencies from RYGB 2–3 years after surgery (105) Iron deficiency Vitamin B12 deficiency Calcium deficiency Vitamin D deficiency Fat-soluble vitamin deficiencies (A.28% (n 5 84. Most of these studies. and remission/improvement was 63% for hypertension.. and outcomes 1–2 1–4 Cardiopulmonary events (105) . all but two of these studies support a lower CVD event rate and all-cause mortality rate among patients who had undergone bariatric surgery. and varied by type of procedure. Among 60 patients with mild type 2 diabetes mellitus and a BMI of 30 to Fox and Associates 40 kg/m2.001). A systematic review of long-term cardiovascular risk factor reduction after bariatric surgery involved 73 studies and 19. however. Resolution was typically defined as becoming nondiabetic with normal A1c without medications. 1785 . the average excess weight loss for all procedures was 54%.6. Roux-en-Y gastric bypass. 12 cohortmatched studies comparing bariatric surgery with nonsurgical controls were reviewed (99). Thromboembolic disease (105) 0.6% with or without medications) after Roux-en-Y gastric bypass (42%) or sleeve gastrectomy (37%) compared with intensive medical therapy (12%) at 1 year (P . Of these studies. with few major complications.35% (n 5 19. and neuropathy in type 2 diabetes mellitus. K) and protein calorie malnutrition from BPD and DS procedures Surgical revision required in as many as 20 within 5 years 15 2–5 1–2 1–5 1–5 1–2 45–52 8–37 10 51 1–5 AGB. The Longitudinal Assessment of Bariatric Surgery (LABS) study subsequently reported a similarly low 30-day mortality rate (0. Both surgical procedures resulted in greater improvement in other CVD risk factors. adjustable gastric banding produced larger reductions in weight.002) despite a greater prevalence of smoking and higher baseline weights and blood pressures in the surgical cohort (92). P 5 0. with follow-up of only 1 to 3 years on average. BPD. for the nonsurgical control subjects (P .928) (104). the remission rate for type 2 diabetes mellitus was 72% at 2 years and 36% at 10 years compared with 21% and 13%. Few. The safety of bariatric surgery is of primary concern in the determination of whether the potential benefits outweigh the surgical risks. nephropathy. These issues represent important future areas of research. CVD mortality in the surgical group was lower than for control patients (adjusted HR 0. mostly retrospective. D.diabetesjournals.3% incidence of major adverse events in the early postoperative period. were retrospective. Two other RCTs in patients with obesity and type 2 diabetes mellitus consisting of 60 (102) and 120 (103) patients demonstrated similar results.776 patients (105). A1c.76]. the SOS study has the longest outcomes follow-up (median 14. A meta-analysis involving 19 studies (mostly observational) and 4. A larger RCT of 150 patients with mild to moderate obesity (BMI 27–43 kg/m2) and poorly controlled type 2 diabetes mellitus (mean A1c 9%) (101) demonstrated better glycemic control (defined as A1c . with a relative risk reduction of 78% (96). Although these reports are encouraging. Recently.org with severe obesity (BMI $35 kg/m2) after weight loss procedures.and long-term perioperative morbidity rates for bariatric surgery are lower than might be expected for this medically comorbid population. compared with intensive medical therapy. duodenal switch. At a mean follow-up of 57. an effect rarely equaled by medical treatment alone. and resulted in both superior glycemic control and greater improvements in CVD risk factors compared with medical treatment alone in up to 24 months of follow-up. DS. a number of complications associated with bariatric surgery are potentially fatal and merit careful consideration. and 65% for hyperlipidemia. Bariatric surgery can reverse or improve many obesity-related disease Table 7—Complications of bariatric surgery Complications Sepsis from anastomotic leak (105) Hemorrhage (105) Frequency.29–0. respectively. and diabetes mellitus medication use compared with medical treatment and achieved remission (defined as A1c . A1c typically improved from baseline by a minimum of 1% up to 3% after surgery. RCT Data.7 years). %.3% without medications) rates of 73% compared with only 13% for medical management (P . biliopancreatic diversion. Collectively. The results are far from conclusive but suggest a potential reversal in or reduced development of nephropathy after bariatric surgery (97.001) (95). All four RCTs showed that surgery in the short term (1–2 years) was well tolerated.05) (100).3%) among 4. including triglycerides and HDL-C. 0. the LABS Consortium reported a 4.070 patients reported an overall type 2 diabetes mellitus resolution rate of 78% after bariatric surgery (93). In the SOS study. 73% for type 2 diabetes mellitus. with larger reductions in CHD events for men and larger reductions in stroke for women. for women. Aspirin reduces CVD events in patients with known CVD (secondary prevention) (106). Recommendations 1. A separate meta-analysis of both primary and secondary prevention trials did not find a difference in the efficacy of aspirin in diabetes mellitus according to dose (119). The net effect of aspirin therefore depends on the baseline risks of CVD events and (gastrointestinal) bleeding. In the general primary prevention population.to 4-fold increased risk of CVD. but further modeling work and better data on sex-specific effects of aspirin are needed. After adjustment for other CVD risk factors. September 2015 Overall. with event rates correlating with the degree of hyperglycemia (126. Low-dose aspirin is reasonable in adults with diabetes mellitus at intermediate risk (10-year CVD risk. Taken as a whole. The range of underlying CVD risk varied widely across trials. Zhang et al. However. Conversely. Trials examining the effect of aspirin for primary prevention in patients with diabetes mellitus are summarized: six trials (108–113) were conducted in the general population that also included patients with diabetes mellitus.and medium-term CVD. The available analyses differ somewhat in the trials they included. every 1-mmol/L (18mg/dL) increase in fasting plasma glucose predicted a 17% increase in the risk of future cardiovascular events or death (128).50% women. The durability of these metabolic improvements.71 and a relative risk for stroke of 1. Risk of bleeding appeared to be increased $2-fold but was not statistically significant in any meta-analysis.05 with aspirin use compared with nonuse (117). A1C TARGETS IN TYPE 2 DIABETES MELLITUS Observational Data Type 2 diabetes mellitus is associated with a 2. an increase of 1% in A1c was associated with an increased risk of 18% in CVD events (129). and CVD risk factor improvement. but aspirin appears to reduce the risk of stroke (107).127). Through 2012. Participants were mainly late middle-aged adults. In the DCCT. the correlation between hyperglycemia and microvascular disease is much stronger than that for macrovascular disease. aspirin is effective in preventing nonfatal myocardial infarction (MI) in men (106). in various measures of microvascular and neuropathic complications from more intensive control of glycemia in type 1 and type 2 diabetes mellitus. Taken together. Level of Evidence B) (ADA Level of Evidence C). Trials ranged from 3 to 10 years in duration and have examined a wide range of aspirin doses. the seven analyses suggest at best a modest effect of aspirin. the Diabetes Control and Complications Trial (DCCT) (made up of individuals with type 1 diabetes mellitus) and the UK Prospective Diabetes Study (UKPDS) found highly significant reductions.112) included only men. There is now evidence supporting decreases in short. Participants previously randomized to the intensive arm experienced a 42% reduction . mainly from the gastrointestinal system.133). the risk of MI was 1. particularly from the RCT literature. ASPIRIN THERAPY Whether to use aspirin for the primary prevention of CVD events in patients with diabetes mellitus remains controversial. but the numbers of events were small and not significantly different (8). A1c improvement.117–122).121. Benefits should be weighed against short. including type 2 diabetes mellitus.1786 Scientific Statement processes. Modeling using data from studies of general middle-aged adults suggests that aspirin is highly beneficial when the 10-year risk of CVD events is . the evidence is less clear. However.25% annual CHD risk).67 with aspirin use compared with nonuse. these data highlight how bariatric surgery can result in weight loss. although these data are derived from observational studies only. with statistically nonsignificant risk reductions of 10% each for the key individual outcomes of stroke and MI. For example. CIs were narrower and sometimes statistically significant. (117) found that for trials with . When analyses examined total CVD events (MI and stroke together). Some analyses found evidence for sex-related differences in outcomes (117. ranging from 25% to 70%.109. over time remains to be determined and represents an important future area of research. Randomized. 5–10%) (ACC/AHA Class IIb. Level of Evidence C) (ADA Level of Evidence E).131).5 years. Significant reductions in CVD events emerged nearly 10 years after the study ended despite subsequent similar mean A1c levels (8%) in both groups during follow-up of the DCCT cohort (the Epidemiology of Diabetes Interventions and Complications [EDIC] study).122). and three other trials (114–116) specifically examined patients with diabetes mellitus. and 12% to 14% in all-cause mortality (130. three trials (108. Bariatric surgery may be particularly suitable for patients with type 2 diabetes mellitus and severe obesity (BMI $35 kg/m2) because these patients may benefit from obesity comorbidity improvement and significantly improved glycemic control compared with medical therapy alone. Specific recommendations based on current clinical guidelines for aspirin administration in adults with diabetes mellitus and no preexisting CVD are summarized (120). the evidence that intensive glycemic control reduces this risk is limited compared with the well-proven risk reduction in microvascular and neuropathic complications (8. Participants in the Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) trial were at very low risk (0.10 and the risk of stroke 0. Diabetes Care Volume 38. It is likely that such a benefit also accrues to patients with diabetes mellitus. In a large multiethnic cohort. which are best managed by a long-term multidisciplinary effort. these results suggest a modest (9%) relative reduction in risk for CVD events and $2-fold relative risk of bleeding.125).10% and the baseline risk of gastrointestinal bleeding is not increased (124. with a 37% increase in the risk of retinopathy or renal failure associated with a similar 1% increase in A1c (132).133). Clinical Trials Looking at A1c Level and Incident CVD Despite the strong link between hyperglycemia and CVD risk. neither study could demonstrate significant CVD risk reduction during the period of randomized intervention. whereas earlier trials had control group CHD risks exceeding 2%/year. 19% in MI (129). trials with $50% men had a relative risk for CHD events of 0.and long-term complications. seven meta-analyses have synthesized data on the effects of aspirin for patients with diabetes mellitus (106. Low-dose aspirin (75–162 mg/day) is reasonable among those with a 10year CVD risk of at least 10% and without an increased risk of bleeding (ACC/ AHA Class IIa. 2. the number of CVD cases was fewer in the intensive group (mean achieved hemoglobin A1c 7%) compared with standard control (9%) after a mean treatment duration of 6. respectively (8. but no significant effect on mortality (144–147). subgroup analyses of VADT.4% in the standard arms) on macrovascular outcomes.01) reduction in MI became significant only after 10 years of observational follow-up of the UKPDS population.149). this approximate risk (15%. A meta-analysis of trials of intensive glycemic control suggests that glucose lowering may have a modest but statistically significant reduction in major CVD outcomes. stroke. P 5 0.22 [95% CI 1. or CVD death compared with those in the standard arm (134). despite the convergence of mean A1c soon after the randomized component of the study ended (135). with no reduction in the macrovascular outcome (138). Three large trials in type 2 diabetes mellitus were designed to address continuing uncertainty (136) about the effects of even more intensive glycemic control on CVD outcomes and reported results in 2008: the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study (137). Meta-analyses also found evidence of reduced CVD with metformin therapy (150. A post hoc analysis found that VADT participants with a duration of diabetes mellitus of . comparison of the mortality findings in ACCORD and ADVANCE.0–8. None of the trials could demonstrate any significant reduction in the primary combined cardiovascular end points. whereas those with a duration of .4%) to those in ACCORD. The first evidence for a CVD benefit of metformin came from a small UKPDS substudy involving 753 overweight patients. Glucose-Lowering Agent Selection for CVD Risk Reduction Metformin is widely accepted as the firstchoice agent for glycemic lowering because it does not cause weight gain or hypoglycemia and may improve CVD outcomes (59). any such benefit of glucose lowering on CVD in type 2 diabetes mellitus is slight compared with the treatment of other CVD risk factors. and there was less hypoglycemia. Within the intensive arm. These analyses suggest that the potential risks of intensive glycemic control may outweigh its benefits in certain individuals such as those with a long duration of diabetes mellitus.0% versus 7. and other post hoc analyses. which found a relative risk reduction of 39% in MI in the group assigned to metformin versus conventional therapy (10). a known history of severe hypoglycemia. and the Veterans Affairs Diabetes Trial (VADT) (139). ADVANCE participants at entry had a shorter duration of diabetes mellitus. All three studied middle-aged or older (mean age 60–68 years) participants with established type 2 diabetes mellitus (mean duration 8–11 years) and either known CVD or multiple major CVD risk factors.20 years had higher mortality with the more intensive strategy (143). advanced atherosclerosis. a composite of CVD events.4%). a lower A1c. Another small study found an adjusted HR of 0.01–1. However. and CVD death). Exploratory analyses were unable to link the increased deaths to weight gain. primarily the development of macroalbuminuria.care. The increased mortality in the ACCORD intensive arm compared with the standard arm (1. VADT randomized participants with poorly controlled type 2 diabetes mellitus (median A1c at entry 9. stroke. rapid lowering of A1c.02) in nonfatal MI. The study results and post hoc analyses have been comprehensively reviewed and analyzed in a scientific statement of the ACC Foundation and AHA/position statement of the ADA (140). This study assessed CVD outcomes from the provision of sufficient basal insulin to normalize fasting plasma glucose levels in people $50 years of age with impaired fasting glucose. Thus. HR 1.6 years.46]) was predominantly cardiovascular in nature and occurred in all prespecified subgroups.151). The study found a nonsignificant trend (16% risk reduction.org (P 5 0.026) for a composite CVD outcome in patients with type 2 diabetes mellitus and coronary artery disease (CAD) who received metformin compared with glipizide (152).052) toward reduced MI with the more intensive strategy after 10 years (133). Fox and Associates Although hypoglycemia was more frequent in the intensive arm. Early use of basal insulin achieved normal fasting plasma glucose levels in the trial but had no effect on CVD outcomes compared with guideline-suggested glycemic control (148). this was attributable solely to a significant reduction in the microvascular outcome. However.41%/year versus 1.9% lower in the intensive group (7. the Action in Diabetes and Vascular Disease: Preterax and Diamicron ModifiedRelease Controlled Evaluation (ADVANCE) trial (138). participants with the highest A1c levels during the trial actually had the highest risk for mortality. impaired glucose tolerance. and a limited life span because of advanced age. ACCORD was stopped early as a result of increased mortality in the intensive group. Current recommendations for glucose-lowering and A1c targets can be found in Table 5. compared with ACCORD subjects. or early type 2 diabetes mellitus and other CVD risk factors.4–6.15 years had a mortality benefit in the intensive arm. the association of severe hypoglycemia with mortality was stronger in the standard control arm (141). hypoglycemia. although the median A1c level achieved in intensively treated patients was similar (6.54 (P 5 0. intensive glycemic control significantly reduced the primary outcome.9%) or standard glycemic control (achieved A1c 8.14%/year. or comorbid conditions (59. However. The overall A1c achieved was 0.4%) to a strategy of intensive glycemic control (achieved A1c 6. or use of any specific drug or drug combination. The Outcome Reduction With an Initial Glargine Intervention (ORIGIN) trial studied glucose lowering earlier in the course of type 2 diabetes mellitus.diabetesjournals.02) in CVD outcomes and a 57% reduction (P 5 0. As in the DCCT/EDIC. primarily nonfatal MI. a combination of microvascular events (nephropathy and retinopathy) and major adverse CVD events (MI. P 5 0.9%). increased mortality in ACCORD was associated with individuals who were assigned to the intensive glycemic control group but ultimately failed to achieve intensive glycemic control (142). frailty. 1787 . there was no significant difference in the cumulative primary outcome. After 5. They compared the effects of two levels of glycemic control (median A1c 6. In ADVANCE. The UKPDS randomized participants newly diagnosed with type 2 diabetes mellitus to intensive (with sulfonylureas or insulin) compared with conventional therapy.9% in the intensive arms compared with 7. glucose was lowered less rapidly in ADVANCE. Recommendations for A1c Targets for CVD Event Reduction Recommendations for individualization of therapeutic targets have drawn from considerations of the time required for microvascular risk reduction to alter rates of clinically significant vision loss or kidney dysfunction. There was no difference in overall or CVD mortality between the intensive and standard glycemic control arms in ADVANCE. and less use of insulin. The four drugs will also be compared with respect to durability. several large trials are currently under way to test the cardiovascular safety and efficacy of newer antihyperglycemic therapies. counterregulatory hormones are released. and cardiovascular mortality) was modestly reduced by 16% (HR 0.pdf). dipeptidyl peptidase-4 inhibitors) and the sodium– glucose cotransporter-2 inhibitors.S. coma. population-based data indicate that the overall incidence of hypoglycemia in insulin-treated type 2 diabetes mellitus is approximately one-third of that in type 1 diabetes mellitus (164). and insulin) in combination with metformin in 5. particularly those with long-standing disease (163). Although most commonly associated with insulin therapy. most studies are of short duration and focus on glycemic lowering and side effects rather than CVD outcomes. P 5 0. When glucose falls below 70 mg/dL. Another thiazolidinedione. Finally.5 years had incidences of 10 and 70 episodes per 100 patientyears. An acarbose trial (Acarbose Cardiovascular Evaluation [ACE]) is currently being conducted in China to determine whether this apparent benefit can be replicated in patients with already established type 2 diabetes mellitus. glucagon-like peptide-1 receptor agonists. respectively (165).27. systolic blood pressure. including cost and quality of life. Patients with type 2 diabetes mellitus treated with insulin for . Patients with repeated episodes of hypoglycemia are at increased risk of deficient counterregulation and loss of self-awareness of hypoglycemia. Of note. In most circumstances. These may produce symptoms such as tremor. but hospitalization for heart failure was significantly higher with saxagliptin (3. and cost-effectiveness. putting them at increased risk for seizures. P 5 0. stroke. and this has clouded the issue concerning the potential benefits of this insulin-sensitizer drug class in atherosclerosis. Food and Drug Administration mandate.28–0. There are several mechanisms by which hypoglycemia might promote adverse cardiovascular outcomes in highrisk individuals (168. there are limited data on the comparative effectiveness of the many other effective antihyperglycemic drugs. tolerability. and headache.15 years had 110 and 320 episodes of severe hypoglycemia per 100 patientyears. adverse effects. there are no convincing data to suggest that any single type of antihyperglycemic therapy in type 2 diabetes mellitus has a CVD advantage over another other than perhaps metformin (159). dipeptidyl peptidase-4 inhibitors. or even death (166. respectively (165). as glucose approaches this level. HYPOGLYCEMIA AS A CVD RISK FACTOR IN TYPE 2 DIABETES MELLITUS Incidence of Hypoglycemia Hypoglycemia is the most common adverse effect of insulin therapy and a major factor limiting glucose control in many patients with type 2 diabetes mellitus.5% versus 2. Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care in Patients With Type 2 Diabetes Mellitus and Acute Coronary Syndrome (EXAMINE) randomized 5.1788 Scientific Statement Beyond metformin. there is lingering controversy as to whether rosiglitazone may actually increase the risk of MI (156.03) in patients with impaired glucose tolerance (158). rates of ischemic events were similar with saxagliptin and placebo. New Glucose-Lowering Medications and CVD Risk U.gov/downloads/ Drugs/GuidanceComplianceRegulatory Information/Guidances/ucm071627 . Two exceptions deserve mention.98]. providers should consider not only efficacy in glycemic control but also safety. in a diabetes mellitus prevention trial.S. quality of life.84 [95% CI 0. At a median follow-up of 2. The incidence of hypoglycemia increases with the duration of insulin therapy. and performance of physical tasks. hypoglycemia is also a side effect of insulin secretagogs such as sulfonylurea and glinides. . However. Two Diabetes Care Volume 38. CVD risk factors. in choosing among available therapies. which may alter behavior and impair cognition. endogenous insulin secretion stops. the occurrence of hypoglycemia unawareness limits the determination of the true incidence of this self-reported condition. although an increase in heart failure has been observed (154). the a-glucosidase inhibitor acarbose was associated with a 49% relative reduction in cardiovascular events (HR 0. Prospective.5 or . and outcomes that matter most to patients. Food and Drug Administration guidance now requests evidence that new glucose-lowering therapies are not associated with an increase in cardiovascular risk in patients with type 2 diabetes mellitus (159) (www.51 [95% CI 0.007) (160). Therefore. tachycardia. a secondary outcome (MI.027).fda. whereas milder episodes may be self-treated.157).95]. P 5 0. Indeed.8%. Hemodynamic changes after autonomic activation induced by hypoglycemia include increases in heart rate. Study To Prevent Non-insulinDependent Diabetes Mellitus (STOPNIDDM). Mechanisms of Hypoglycemia and CVD Although the lower range of normal postprandial glucose is 70 mg/dL. anxiety. Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus– Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) randomized 16.169). When added to baseline antihyperglycemic therapy regimens in the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive). To date.2 or . rosiglitazone. both studies were designed to demonstrate noninferiority of the study drugs and enrolled patients with established CHD to achieve adequate event rates with a relatively short duration of follow-up.1 years. which was a broad cardiovascular composite that include peripheral vascular events (153). the rates of CVD events were similar in the treatment and placebo arms. As in SAVORTIMI 53. adverse effects such as weight gain and hypoglycemia. diaphoresis. As a result.492 patients.000 subjects with an anticipated observation period of 4 to 7 years. September 2015 publications on the cardiovascular safety of dipeptidyl peptidase-4 inhibitors are the result of this U.72–0. Severe hypoglycemia is defined as an event requiring external assistance for recovery. judgment. pioglitazone had no apparent benefit on the primary end point. these warning symptoms prompt patients to ingest glucose or other carbohydrates to protect against neuroglycopenia. HR 1. The UK Hypoglycemia Study Group found that patients with type 1 diabetes mellitus with an insulin therapy duration . selected microvascular complications. and autonomic neural activation occurs.380 patients with a mean duration of followup of 18 months (161). hunger. The Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) (162) will compare glycemic lowering of four commonly used classes of diabetes mellitus medications (sulfonylureas.167). has been shown to have no such effect (155). including incretin-based drugs (glucagon-like peptide-1 receptor agonists. However. secondary analyses did not establish hypoglycemia as the cause of the increased mortality in the intensive group (141. Thus. Additionally.173). The UKPDS (133) had a severe hypoglycemia rate of 1. including CVD mortality. In ADVANCE and VADT.178). fatal and nonfatal stroke. rates of severe hypoglycemia and death were increased with intensive treatment. and VADT (139) randomized nearly 24.6 years. including major microvascular events.001). These studies did not find any substantive benefit of intensive blood pressure control (systolic blood pressure . Two studies of intensive glycemic control earlier in the course of type 2 diabetes mellitus were also associated with an increased risk of hypoglycemia compared with standard therapy.178). and various microvascular events. The presence of hypertension in patients with type 2 diabetes mellitus increases the risk of MI. In ACCORD. avoidance of hypoglycemia is a key goal of diabetes mellitus management. although the absolute rates were low.4 to 5. death resulting from any cause.2% versus 9. a complication of long-standing diabetes mellitus. and arrhythmias have been reported during severe episodes (170).2% versus 5. In ADVANCE. stroke. and older studies did not address the more contemporary questions of usual compared with intensive blood pressure lowering on CVD risk.172). rates of severe hypoglycemia were substantially higher with intensive compared with standard therapy in all three trials: 16. hypoglycemia is a serious and common complication of diabetes mellitus management and is associated with CVD events and mortality.70 mg/dL) identified by self-monitoring of blood glucose was associated with a small but statistically significant reduction in mortality in the intensive but not the standard group (175). more frequent Fox and Associates hypoglycemia (. In addition.7%/year in the standard control group. younger age of participants. starting as low as 115 mmHg (176–178). with a modest and nearly significant reduction in CVD event rate (P 5 0. nephropathy. nonfatal MI. and coagulation while increasing inflammatory mediators and blood viscosity and lowering potassium levels (171. Data From Recent RCTs on Intensive Blood Pressure Lowering in Type 2 Diabetes Mellitus Several recent RCTs have specifically examined the role of an intensive blood pressure–lowering strategy to achieve systolic blood pressure . and less use of insulin likely contributed to the lower rates of hypoglycemia in ADVANCE. Together. hypoglycemia has additionally been reported to have deleterious effects on endothelial function. It is important to recognize. UKPDS. digestive. Patients treated with insulin or insulin secretagogs should be queried regularly about the occurrence of hypoglycemia. Although the A1c goals for intensive and standard therapy differed among the trials. In ORIGIN (148).7% in VADT. the coexistence of both conditions increases the risk of developing heart failure. 2. however.31 per 100 person-years in the standard care group. however. In summary.diabetesjournals. Although secondary analyses could not exclude the possibility that severe hypoglycemia had a direct causal link with death. ACCORD (137). 0. may contribute to arrhythmias and the risk of sudden death in individuals with diabetes mellitus. The ACCORD study randomized 4. severe hypoglycemia was associated not only with an increased risk of cardiovascular events and death but also with a wide range of other adverse outcomes.174).140 mmHg) 1789 . Finally. but annual mortality among patients who reported severe hypoglycemia was actually higher in the group receiving standard treatment than in the group receiving intensive treatment (141. and 21. the investigators have concluded that hypoglycemia was likely serving as a marker of inherent vulnerability to adverse clinical outcomes. intensive glucose control was not associated with excess mortality. severe hypoglycemia was a risk factor for mortality. platelet reactivity.1% in ACCORD. Epidemiological observations from landmark studies such as the Multiple Risk Factor Intervention Trial (MRFIT). Although causality is unproven. ADVANCE (138).8%/year in the intensive control versus 0.5% in ADVANCE.120 mmHg) or usual therapy (systolic blood pressure . including nephropathy (179. An interaction of hypoglycemia-induced abnormalities of cardiac repolarization with autonomic neuropathy.130 mmHg (in patients with diabetes mellitus and hypertension) on various outcomes. glycemic control therapies that increased the risk of hypoglycemia do not appear to be associated with an increased risk of cardiovascular events.052) in the intensive group. and nonvascular outcomes such as respiratory.733 patients with type 2 diabetes mellitus to either intensive blood pressure lowering (defined as systolic blood pressure . A vast majority (70%–80%) of patients with type 2 diabetes mellitus have hypertension.00 per 100 person-years in the insulin-glargine group and 0. Small studies have shown that hypoglycemia induces ischemic and other ECG changes. that in both studies the achieved systolic blood pressure in the aggressive intervention arm was 144 mmHg (113. the majority of whom used no insulin (P .7% versus 1.000 patients to intensive versus standard control with follow-up periods from 3. Whether the use of drugs in type 2 diabetes mellitus associated with lower hypoglycemia risk improves clinical outcomes remains controversial.180). and skin conditions (174). In addition. early in the course of type 2 diabetes mellitus. and cardiac output. Hypoglycemia has also been associated with prolongation of the QT interval. Shorter duration of diabetes mellitus. In both ADVANCE and ACCORD.org myocardial contractility. Hypoglycemia and CVD Events Clinical trials in patients with type 2 diabetes mellitus with or at high risk of CVD have raised concern about the risks of hypoglycemia in this population (140).130 mmHg) in reducing the risk of coronary events defined as fatal or nonfatal MI. the incidence of a first episode of severe hypoglycemia was 1. with no difference in CVD events between the groups.care. and therapy should be adjusted to mitigate its risk.177. BLOOD PRESSURE LOWERING IN TYPE 2 DIABETES MELLITUS Increased blood pressure is a major contributor to higher risk of CVD events in diabetes mellitus. and all-cause mortality. some of the earlier interventional RCTs (UKPDS and Hypertension Optimal Treatment [HOT]) have demonstrated the benefit of aggressive blood pressure reduction in lowering the risk of both macrovascular and microvascular events (113. These effects may exacerbate ischemia in individuals with occlusive CAD. and others have demonstrated that there is a progressive increase in the risk of macrovascular and microvascular events with increasing levels of systolic blood pressure. all-cause mortality. and other microvascular events (176). it is difficult to define a universal target blood pressure goal for all patients with type 2 diabetes mellitus and hypertension (183). nonfatal stroke.91 [99% CI 0. However. Additionally. in patients with type 2 diabetes mellitus and hypertension. it may be beneficial to reduce systolic blood pressure to targets lower than recommended for the general diabetes mellitus population. the ADVANCE trial tested the effect of a fixed combination of perindopril and indapamide (180). the effects may also vary on the basis of the presence or absence of comorbid conditions in a given individual and the subsequent risk of events (183). along with the new recommendations from the panel members appointed to the Eighth Joint National Committee and the ADA (4. The updated report from the panel members appointed to the Eighth Joint National Committee now recommends that target blood pressure be . the primary study outcome was a composite end point of nonfatal MI. P 5 0. CHOLESTEROL AND LIPOPROTEINS AND CVD RISK IN TYPE 2 DIABETES MELLITUS Lipoprotein Abnormalities in Type 2 Diabetes Mellitus In patients with type 2 diabetes mellitus.736 patients from 13 trials that similarly failed to identify benefit of an intensive blood pressure–lowering strategy over standard blood pressure–control strategy on macrovascular and microvascular (cardiac. Thus.91 [95% CI 0.140/90 mmHg. After 12 months. Similarly. including hypotension. these small. borderline.89. Further studies are necessary to identify the at-risk populations and their appropriate targets. ACCORD and the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET) demonstrated that the use of multiple antihypertensive drugs was associated with an increased incidence of serious adverse effects. Nevertheless. HDL-C is often decreased. or CVD death.04).1790 Scientific Statement (179). However.60. Current clinical recommendations for blood pressure targets in diabetes mellitus can be found in Table 5. clinical trials amply demonstrate that statin treatment will reduce the risk for major coronary events (187). P 5 0.39–0. RCTs are needed to prospectively examine and demonstrate appropriate target blood pressure levels that can be achieved safely and are beneficial in such patients. Taken together.79 [99% CI 0. .3 years demonstrated a 21% proportional reduction in major vascular events per 1-mmol/L (39-mg/dL) reduction in LDL-C in people with diabetes mellitus (relative risk 0. renal. on the basis of newer evidence from RCTs that explicitly tested the benefit of usual versus more intensive blood pressure lowering.140/90 mmHg (61).466 with type 1 and 17.130/80 mmHg (and even lower to 120/75 mmHg in those with renal impairment) (177). neither was significant (macrovascular: HR 0. P . Thus. LDL-C Lowering in Type 2 Diabetes Mellitus LDL-C is identified as the primary target of lipid-lowering therapy. the Diabetes Care Volume 38.140 patients with type 2 diabetes mellitus were randomized to the fixed combination compared with placebo.04]. The Seventh Joint National Committee guidelines recommend that. data from 18.130/80 mmHg in certain individuals if these targets can be achieved safely (4). an association with stroke reduction in the intensive versus usual group was noted (17% reduction in risk).3 years of follow-up.16). the result of the combined primary end point (composite of macrovascular and microvascular outcomes) was significant (HR 0. syncope. if this can be accomplished safely (181. The only significant finding was observed for stroke.01). or normal. LDL particles are small and dense.16. clinical trials that have shown that LDL-C lowering with statins will reduce the risk of major CVD events in patients with or without diabetes mellitus.59 (95% CI 0.0001) and a 9% proportional reduction in all-cause mortality per 1-mmol/L reduction in LDL-C (relative risk 0. P 5 0.81–1. The focus on LDL-C is supported by results of controlled.86].92 [95% CI 0. However.72–0. Moreover. In addition.06]. After 4.3% of the intensive blood pressure–lowering arm compared with 1.3% in the usual care arm (179). Overall.91 [95% CI 0. microvascular: HR 0.183.00]. the relationship between LDL particle size and CVD is confounded by many other CVD risk factors.04]. However. September 2015 ACCORD blood pressure trial found that serious adverse events occurred in 3.88 [95% CI 0. patients in the intervention arm had lower blood pressure (systolic blood pressure 5. P 5 0. In patients at higher risk of stroke who do not have preexisting CHD.73–1. for which the HR was 0. and retinal) events (181) in patients with type 2 diabetes mellitus or impaired fasting glucose. a prespecified secondary end point.184). We note that the ADA recommends blood pressure targets of . Currently.220 with type 2) during a mean follow-up of 4.02) (187). There are additional safety concerns for intensive blood pressure lowering in type 2 diabetes mellitus.83–1.01].82–1. These findings are further corroborated by the results of a meta-analysis of 37. most individuals with diabetes mellitus are recommended to achieve a blood pressure goal of . the target blood pressure should be . triglycerides are often elevated.6 mmHg). data from recent trials do not suggest that intensive lowering of blood pressure in type 2 diabetes mellitus should be implemented as a universal recommendation. Overall. although an elevated LDL-C level generally is not recognized as the major lipid abnormality in patients with type 2 diabetes mellitus. 11.80– 1. It is also important to recognize that the results of statin interventions in patients with diabetes mellitus have demonstrated that the observed benefits were independent of baseline LDL-C and other lipid values. when stratified by macrovascular or microvascular outcomes. Given the appearance of heterogeneity of the effects of intensive blood pressure lowering on coronary compared with cerebral events.182).20).61). dense LDL particles may be more atherogenic than would be suspected by their concentration alone because in vitro and cell culture studies suggest that they may be more readily oxidized and glycated (185). P 5 0. similar results were observed for death resulting from all causes. there was no difference in the primary end point (HR 0. the LDL-C concentration may be misleading because there will be more LDL particles for any cholesterol concentration. 0. and LDL-C may be elevated. targeting changes in LDL size to reduce CVD risk is not indicated (186). These outcomes were similar to those achieved in patients without diabetes mellitus. Most patients with type 2 diabetes mellitus and hypertension require multiple pharmacological agents to obtain adequate blood pressure control. P 5 0. Specifically. systolic blood pressure was 119 mmHg in the intensive blood pressure– lowering arm compared with 133 mmHg in the usual care arm.686 individuals with diabetes mellitus (1. and worsening renal function (179. the data do not support a recommendation that patients with diabetes mellitus on a statin with fasting plasma triglycerides . that is. appear to be atherogenic. a trial of niacin in statin-treated patients with known CVD. and represent a secondary target of lipid-lowering therapy. Four major fibrate trials in which patients with CHD or diabetes mellitus have been included have been completed. and as in VA-HIT. According to the National Cholesterol Education Program Adult Treatment Panel III. between 40 and 75 years of age. nonfatal MI. and the overall findings are hypothesis generating at best. the 2013 ACC/AHA guidelines on the treatment of cholesterol to reduce atherosclerotic cardiovascular risk in adults provide no evidence-based recommendations for the evaluation or treatment of hypertriglyceridemia to reduce of CVD risk (62). no patients were on statins (189). The trial was stopped after a mean follow-up period of 3 years because of a lack of efficacy. HDL-C increased from a baseline of 42 mg/dL by 31% to 40% and by 4% to 11% in the placebo group without LDL-C lowering in either group. post hoc analyses of all three trials suggested that those patients with hypertriglyceridemia with (FIELD. CKD is common and is associated with adverse health outcomes. Despite the lack of benefit of a fibrate in patients with diabetes mellitus in BIP. the primary end point of CVD events or hospitalization for unstable angina was no different in the niacin versus the placebo group. we are left with post hoc analyses that could potentially help guide the design of the optimal trial to follow. In the Action to Control Cardiovascular Risk in Diabetes Lipid Trial (ACCORDLIPID). and lowered LDL-C from 74 to 62 mg/dL. Presently. Unfortunately. and gemfibrozil was the fibrate chosen. This and additional guidelines for statin therapy are summarized in Table 5. At 2 years.org Triglyceride Lowering in Type 2 Diabetes Mellitus Triglyceride-rich lipoproteins.care. all patients with diabetes mellitus and LDL-C levels between 70 and 189 mg/dL should be treated with a statin. or cardiac arrest with resuscitation. an effect mostly demonstrated in the 25% of patients with diabetes mellitus (188). In patients with diabetes mellitus who are . HDL-C is not a target for therapy according to the ACC/AHA cholesterol treatment guidelines (62). including patients with diabetes mellitus. Another HDLC–raising trial.871 patients who had experienced a recent acute coronary syndrome. whereas the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial was conducted exclusively in patients with diabetes mellitus with a statin drop-in rate of 23% in the placebo group and 14% in the fenofibrate group (190). Although the ADA recognizes serum triglycerides as a surrogate for atherogenic triglyceride-rich lipoproteins and suggests a target of . and ACCORD-LIPID. On dalcetrapib. The primary end point was a composite of death resulting from CHD. Kidney Disease in Diabetes Mellitus In type 2 diabetes mellitus. included 34% of patients with diabetes mellitus (192). Recommendations for Lipid Management in Type 2 Diabetes Mellitus In adult patients with diabetes mellitus. especially weight reduction. and increases in dietary fiber and physical activity. Although CKD in most 1791 .40 years of age without overt CVD.414 patients were randomly assigned to receive niacin or placebo. especially VLDL.500 mg/dL to prevent more severe hypertriglyceridemia and pancreatitis (62). and 25% had diabetes mellitus (193). At best. weight loss (if indicated). A total of 3. We note that ADA clinical practice guidelines indicate that “combination therapy (statin/fibrate and statin/niacin) has not been shown to provide additional cardiovascular benefit above statin therapy alone and is not generally recommended” (Level of Evidence A) (4). The most selective of the triglyceride-reducing drugs are the fibrates. the new ACC/AHA cholesterol guidelines indicate that there is strong evidence that moderate-intensity statin therapy should be initiated or continued for adults 40 to 75 years of age or high-intensity statin should be started if the individual calculated risk is high. this goal is non–HDL-C (40). However. such trials have suffered from inadequate experimental design and are few in number. ACCORD-LIPID) or without (BIP) low levels of HDL-C appeared to benefit. lowered triglycerides from 164 to 122 mg/dL.150 mg/dL (4).200 mg/dL have reduced CVD risk with the addition of a fibrate. was carried out in 15. unstable angina. SCREENING FOR RENAL AND CARDIOVASCULAR COMPLICATIONS This section provides the evidence base for screening for CVD and renal complications in type 2 diabetes mellitus. Lifestyle modification deserves primary emphasis in all patients with diabetes mellitus with a focus on the reduction of saturated and trans fat intake. the ADA considers levels of HDL-C . These lifestyle changes. which used the cholesterol ester transfer protein inhibitor dalcetrapib. Moreover. however.diabetesjournals. this trial was terminated for futility with no evidence of CVD risk reduction in the entire cohort. As in AIM-HIGH. The Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT) was carried out in men with known CVD and low levels of HDL-C (. in hypertriglyceridemic patients with diabetes mellitus with or without statin therapy. The ADA 2015 practice guidelines are now concordant with the AHA guidelines (4). all patients had diabetes mellitus Fox and Associates and were on simvastatin (191). have been shown to improve most components of the lipid profile in patients with diabetes mellitus (194). lipid levels should be measured at least annually for compliance with recommended treatment.40 mg/dL). However. Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/ High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH). consistent with the National Cholesterol Education Program Adult Treatment Panel III guidelines. are often elevated in patients with diabetes mellitus. niacin increased the median HDL-C from 35 to 42 mg/dL. Briefly.50 mg/dL in women desirable (4). ischemic stroke. HDL Raising in Type 2 Diabetes Mellitus Currently. The Bezafibrate Infarction Prevention (BIP) had a minority of patients with diabetes mellitus. Clinical trials conducted to date do not support triglyceride reduction in the presence or absence of diabetes mellitus as a means to reduce CVD risk. FIELD. the panel continued to endorse the evaluation and treatment of patients with fasting triglycerides .40 mg/dL in men and . VA-HIT was the only fibrate study to demonstrate a significant benefit of a fibrate on CVD. outcomes in patients with diabetes mellitus appeared to be similar to those in patients without diabetes mellitus. as reviewed earlier. This recommendation includes measurement of both urine albumin excretion. In older studies. In particular. widespread screening for silent CAD in diabetes mellitus cannot be recommended at this time (209).5%: 16. Further testing of patients with diabetes mellitus and abnormal ECG findings for inducible ischemia is currently endorsed by the professional societies (210). when disease is advanced.210). whereas a recent meta-analysis reported that evidence for cardiovascular benefit was strongest for angiotensin-converting enzyme inhibitors (204). renin-angiotensin system inhibitors Diabetes Care Volume 38. As a result.. Goals of care for patients with DKD include preventing progression to endstage renal disease and reducing the risks of cardiovascular events and death. September 2015 reduce the risks of progression to endstage renal disease. In the UKPDS.S. Although RCTs of screening versus not screening have not been conducted (200). acute kidney injury. However. the ACCORD trial did not demonstrate that a lower blood pressure target significantly improved renal or cardiovascular outcomes overall (179). inexpensive.196). Patients with DKD may also have reduced longevity. Additional studies are required to define the impact of DKD on other common diabetes mellitus– related interventions. the high prevalence of abnormal ECG findings in patients with type 2 diabetes mellitus. approaching 20% (212). A variety of CAD screening tests (211– 229) are available (Table 8). 10. However. and their association with morbid outcomes.. the use of ECGs in the risk stratification of patients with type 2 diabetes mellitus appears reasonable (213). In this population. data from UKPDS indicate that an abnormal ECG is an independent risk factor for all-cause mortality and fatal MI in patients with diabetes mellitus (211). the presence of DKD may also be a factor favoring control of blood pressure to low target levels (e. because there is a paucity of data suggesting any specific benefits of invasive interventions over medical therapy alone.60 mL z min21 z 1. in individualized plans for glycemic control.300 mg/g creatinine with normal estimated GFR) or without evidence of DKD. and noninvasive resting ECG. For example.200–202). the prevalence of DKD is 34. the pursuit of revascularization.73 m22). Although the sensitivity and specificity of ECG abnormalities in patients with diabetes mellitus have been questioned (230) and their additive discriminating value on top of known CAD risk factors is marginal. A combination of angiotensinconverting enzyme inhibitors and angiotensin receptor blockers is not recommended because it increases the risk of impaired kidney function and hyperkalemia compared with either agent alone (205– 207). one in six patients with newly diagnosed type 2 diabetes mellitus had evidence of silent MI on the baseline surface ECG (211). in the ACCORD trial. most conveniently measured as the ratio of albumin to creatinine in a single-voided urine sample. Among adults with diabetes mellitus in the U. the risk of severe hypoglycemia associated with intensive glucose control was increased among participants with greater urine albumin excretion or higher serum creatinine concentration measured at baseline (173). A head-to-head comparison of an angiotensin-converting enzyme inhibitor and an angiotensin receptor blocker in type 2 diabetes mellitus with elevated urine albumin excretion suggested that the effects on CKD progression were clinically equivalent (203). the detection of disease before acute coronary syndrome events may improve morbidity and mortality. Subclinical CAD Assessment Identification of asymptomatic CAD may allow the opportunity for more aggressive lifestyle or pharmacological interventions to prevent clinical events or. Clinical manifestations of DKD include elevated urine albumin excretion (albuminuria) and impaired glomerular filtration rate (GFR) (4. but clinical trials conducted among such patients have not demonstrated improvements in hard renal or cardiovascular outcomes. including CVD (196). Given the wide availability and low cost of ECGs.e. so they may not reap the long-term benefits of tight glucose control. on the basis of the considerations above (4. CVD events. Among people with or without diabetes mellitus. The staging of DKD according to the Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline links severity of DKD with risks of adverse outcomes. This . albuminuria and impaired GFR are independently and additively associated with increased risks of end-stage renal disease. CAD screening in the asymptomatic patient with diabetes mellitus remains highly controversial (209. These include the simple. and 6. Recent evidence suggests that the presence of DKD identifies a subset of people with type 2 diabetes mellitus who are at markedly increased mortality risk (199). the presence of more advanced DKD may favor less aggressive intervention (205).8% with albuminuria (ratio of urine albumin to creatinine $30 mg/g). Several prior studies have demonstrated that baseline ECG abnormalities are common in asymptomatic patients with diabetes mellitus and no history of CAD. with DKD. beginning at diabetes mellitus diagnosis. The presence of DKD may modify the safety or efficacy of common diabetes mellitus therapies. 130/80 mmHg) in select patients. and death (198). other causes of CKD should be considered when the clinical presentation is atypical because the prognosis and treatment of these diseases may differ from those of diabetic kidney disease (DKD) (195). the ADA and National Kidney Foundation recommend yearly DKD screening for all patients with type 2 diabetes mellitus.195). On the basis of the strong relationship of blood pressure with kidney disease progression. calculated from serum creatinine concentration with a validated formula. the toxicity of some medications may be increased by impaired drug clearance and the presence of more frequent and severe comorbidities. which may detect evidence of prior myocardial injury or ischemia. cardiovascular events.60 mL z min21 z 1. clinical trials provide compelling evidence that people with type 2 diabetes mellitus and substantially elevated urine albumin excretion (i. Because CAD may present in a silent fashion and symptomatic disease is associated with worse clinical outcomes in diabetes mellitus. Renin-angiotensin system inhibitors are also appropriate first-line antihypertensive agents for patients with milder DKD (urine albumin excretion $30 mg/g and .1792 Scientific Statement patients with diabetes mellitus is attributable to diabetes mellitus. the prevalence of ECG abnormalities in patients with diabetes mellitus and no known CAD was even higher. Although it is important to individualize clinical decision making.195. and death (195.9% with both albuminuria and impaired GFR (197).. Whether such a strategy improves patient outcomes remains unknown.g.73 m22) should be treated with an inhibitor of the reninangiotensin system. and GFR.8% with impaired GFR (estimated GFR . $300 mg/g creatinine) or impaired GFR (estimated GFR . Randomized. care. Tc99m sestamibi.4–12. thallium-201. UKPDS data indicate that an abnormal ECG is an independent risk factor for all-cause mortality and fatal MI in patients with diabetes mellitus (211). which.5 years). Stress MPI Radioactive tracer (e.6%. Class III: No benefit.org Fox and Associates Table 8—Screening tests for asymptomatic CAD in patients with diabetes mellitus Test Description Key results Inclusion in a recent AHA guideline? ECG Resting electric activity through the cardiac cycle Class IIa: A resting ECG is reasonable for cardiovascular risk assessment in asymptomatic adults with hypertension or diabetes mellitus (Level of Evidence C) (213). Class IIa: Measurement of ABI is reasonable for cardiovascular risk assessment in asymptomatic adults at intermediate risk (Level of Evidence B) (213).diabetesjournals.g.. ABI Ratio of systolic blood pressure at the ankle and arm. c Silent ischemia prevalence 5 21.73). thus limiting its utility as a screening test for CAD.44–1. QRS prolongation.3]. Stress MPI is not indicated for cardiovascular risk assessment in low.g. Prevalence of ECG abnormalities in patients with diabetes mellitus and no known CAD was even higher in older studies. 8. A systematic review of ABI as a predictor of future CVD events demonstrated high specificity (93%) but very low sensitivity (16%) (215). 522 patients were randomized to adenosine sestamibi SPECT MPI. if positive or equivocal. Continued on p. there was no difference in the primary end point. 15 versus 17 events. nonfatal MI and cardiac death. c Silent CAD prevalence 12. Option for pharmacological stress (dipyridamole. DIAD (217. and pathological T-wave inversions (213). P . or regadenoson) in those not able to exercise MiSAD (216): c A total of 925 asymptomatic patients with type 2 diabetes mellitus underwent an ECG stress testing. HR 0. between the screened and unscreened cohorts (overall annual rate 0. heart failure. Class IIb: Stress MPI may be considered for advanced cardiovascular risk assessment in asymptomatic adults with diabetes mellitus or asymptomatic adults with a strong family history of CHD or when previous risk assessment testing suggests a high risk of CHD (e.88 [95% CI 0. a CAC score of $400) (Level of Evidence C) (213)..80]. stroke. coronary revascularization). adenosine. ST-segment depressions. 0. LVH (particularly if accompanied by repolarization abnormalities). 1. 1794 1793 . c Abnormal scintigraphy predicted cardiac events at 5 years (HR 5. approaching 20% (212).5%.5% for abnormal exercise ECG and 6. Specific ECG abnormalities associated with increased risk of CVD events in cohort studies include pathological Q waves. c No differences in any secondary end points (unstable angina. Used as an indicator of underlying peripheral arterial disease In the UKPDS study.5 [95% CI 2. led to stress thallium MPI.4% for both abnormal ECG and MPI. one in six patients with newly diagnosed type 2 diabetes mellitus had evidence of silent MI on the baseline surface ECG (211).or intermediaterisk asymptomatic adults (Level of Evidence C) (213). Abnormal ECG findings have been demonstrated to predict inducible ischemia (214).001). P 5 0.123 patients with type 2 diabetes mellitus were enrolled from multiple centers (mean duration of diabetes mellitus. and 561 served as the control group and were randomized to follow-up alone. or Tc99m tetrofosmin) uptake within the myocardium is assessed before and after stress with scintigraphy. c At 5 years of follow-up.219): c In total. 400 (high risk) Linear relationship between CAC and clinical CHD events among individuals with and without diabetes mellitus (220–225). Extensive data indicate a linear relationship between CAC and clinical CHD events among individuals with and without diabetes mellitus (220–224). The ankle-brachial index and coronary artery calcium (CAC) scoring by electronbeam computed tomography (CT) are used to detect evidence of atherosclerosis. Furthermore.100. (232) measured CAC in 520 asymptomatic patients with type 2 diabetes mellitus.100 (low risk). test is not currently recommended by the ADA or the U. EBCT. although these methods cannot assess for active or inducible ischemia. CAC scoring Quantitative assessment of calcium deposited within the coronary arteries (as a marker of atherosclerosis) via EBCT or multidetector CT.00 [95% CI 0. and nearly 20% have markedly elevated CAC (225–228). September 2015 Table 8—Continued Test Description Key results Inclusion in a recent AHA guideline? DYNAMIT trial (218): c Prospective. CAC and extent of myocardial ischemia by myocardial perfusion imaging were the only independent predictors of adverse outcomes. and cardiac positron emission tomography. 631 patients were randomized to either CAD screening with either a stress ETT or dipyridamole SPECT MPI versus follow-up only (without screening).S. electron-beam computed tomography. ETT. Prognostic significance of elevated CAC in predicting adverse events is greater in patients with diabetes mellitus than in those without diabetes mellitus (229). In fact. multicenter study conducted in France. patients with diabetes mellitus have a greater prevalence and extent of coronary calcification than those without diabetes mellitus. SPECT. Several studies show that abnormal CAC is correlated with demonstrable myocardial ischemia and predicts future CVD events. 100–400 (moderate risk).100 (low risk). randomized. single-photon emission computed tomography. 16 of whom had abnormal studies. Other screening tests include ECG exercise tolerance testing.2 years. and exercise (or pharmacological) stress echocardiography. but none have had widespread application in asymptomatic patients. ABI. and .59–1. The authors suggested that a 2-staged approach of first identifying . measurement of CAC is reasonable for cardiovascular risk assessment (Level of Evidence B) (213). c In total. moderate to large perfusion defects were seen in 31. and . doubleblind. stratified by Agatston units. Of these. MPI. exercise tolerance testing. left ventricular hypertrophy.71]). yielding CAC scores of . No dedicated randomized trials have suggested that the detection of subclinical CAD by CAC leads to improvement in clinical events. ankle-brachial index. cardiac magnetic resonance imaging. with myocardial perfusion imaging results available in 18 of these individuals. the prognostic significance of elevated CAC in predicting adverse events appears to be greater in patients with diabetes mellitus than in those without diabetes mellitus (229). exercise (or pharmacological) myocardial perfusion imaging (nuclear scintigraphy). 100 to 400 (moderate risk). yielding CAC scores of .400 (high risk). However. Patients with diabetes mellitus have a greater prevalence and extent of CAC than those without diabetes mellitus (225–228). This represents an important area of future research. during which time 20 major adverse cardiovascular events occurred. Table 8 provides a summary overview of several additional screening tests.5% of patients with CAC . no difference in cardiac outcomes was seen between screened and unscreened groups (HR 1.1794 Scientific Statement Diabetes Care Volume 38. can be measured with CT. CAC. In asymptomatic adults with diabetes mellitus $40 years of age. In Cox models. myocardial perfusion imaging. Emerging techniques include CT angiography. although the AHA states that it is reasonable to obtain a resting ECG in asymptomatic adults with diabetes mellitus (Table 8). LVH. Preventive Services Task Force during the initial or followup evaluation of patients with diabetes mellitus because data are lacking that adding an ECG improves risk stratification. along with guideline recommendations from the AHA or ADA. c Study was stopped prematurely. several studies suggest that majority of asymptomatic patients with type 2 diabetes mellitus have coronary calcification. Anand et al. Patients are typically stratified by Agatston units. a marker of intracoronary atherosclerosis. The entire cohort was then followed up for a mean of 2. These findings support the concept that CCTA should not be used for CAD screening in asymptomatic patients with diabetes mellitus. with 0% of patients experiencing adverse cardiac events during 5 years of follow-up (229). However.org the highest-risk patients by CT and then proceeding to screen those individuals with the highest CAC scores with stress scintigraphy would be a more efficient approach than initial myocardial perfusion imaging alone. cardiac magnetic resonance imaging. Fox and Associates The Detection of Ischemia in Asymptomatic Diabetics (DIAD) study is the only prospective. there was no difference in the primary outcome of fatal or nonfatal coronary disease (6.diabetesjournals. which may reflect widespread use of modern CVD risk reduction strategies. no dedicated. the findings from these randomized trials do not support the routine use of nuclear imaging in patients with type 2 diabetes mellitus for subclinical disease CAD screening. It is critical to understand the durability of the remission of diabetes mellitus and other CVD risk factors in longer-term follow-up in the setting of rigorously designed RCTs. 4. Blood pressure lowering: Recent blood pressure trials of tight compared with usual blood pressure targets have failed to identify a cardiovascular benefit. However.232). In addition to CAC. Over a mean of 4 years of follow-up. For these reasons. This conclusion is likely due in part to the very low overall cardiac event rate in DIAD. Although more elaborate. 2.400 may improve outcomes (234). Below. and the results of key studies are summarized in Table 8. The FACTOR 64 trial randomized 900 patients without symptomatic CAD with either type 1 or type 2 diabetes mellitus to CCTA followed by CCTA-directed therapy versus control (standard guideline-based diabetes mellitus management) (235). randomized. Hypoglycemia: Hypoglycemia is a frequent complication of blood glucose lowering in type 2 diabetes mellitus. with or without low HDL-C. we highlight areas that we consider important in advancing CVD prevention in type 2 diabetes mellitus over the next few years: 1. there is a large published experience in screening patients with diabetes mellitus for subclinical CAD with nuclear scintigraphy. and cardiac positron emission tomography.2% in the CCTA group versus 7.6% in the control group. Importantly. because hypoglycemia is difficult to identify comprehensively. particularly on the cardiovascular system. Whether any specific drug class will ever emerge as presenting a clear advantage in this regard is unknown. as demonstrated in several prospective studies (223. Furthermore. SELECTED AREAS OF CONTROVERSY AND FUTURE RESEARCH Several important key areas of controversy require further research. As importantly. CAC not only is an independent predictor of adverse cardiovascular events but also is superior to both the UKPDS risk engine and the Framingham Risk Score in this patient population (229. prespecified secondary analyses have identified a possible protective signal for stroke (179). Bariatric surgery: Bariatric surgery is currently an effective treatment for weight loss. current ACC/AHA guidelines consider CAC reasonable for cardiovascular risk assessment in asymptomatic patients with diabetes mellitus who are $40 years of age (Table 8) (213). however. controlled investigation to rigorously assess the clinical value of screening asymptomatic patients with diabetes mellitus for CAD (219). Further work in high-risk stroke populations is necessary to validate these findings and to determine whether a lower blood pressure target is beneficial in this subpopulation of patients with diabetes mellitus. the lack of benefit remains consistent.care. 5. P 5 0. Other Modalities A number of other noninvasive or semiinvasive tests are currently under study.232). Limited data suggest that CAC influences physicians’ management of CAD risk factors (233). even with more sensitive modalities. the absence of coronary calcium portends a remarkably favorable prognosis despite the presence of diabetes mellitus. Antihyperglycemic therapy: The specific role of antihyperglycemic therapy (in terms of both intensity and specific drug strategy) in reducing cardiovascular events in type 2 diabetes mellitus remains poorly understood. 3. Although an exploratory subgroup analysis from a single randomized. DIAD was able to demonstrate that such a screening strategy is not likely to improve actual clinical outcomes. as with other more traditional tests. However. with a statin background remains to be conducted. the design of this study does not allow an assessment of the ability of this screening paradigm to reduce future coronary events. Thus. There are currently no convincing data to suggest that performing CAC motivates patients to better adhere to lifestyle modifications or medical therapy for CVD prevention. its true prevalence is likely markedly underestimated. Cholesterol lowering: Most lipid guidelines indicate efficacy with statin treatment in patients with type 2 diabetes mellitus. Taken together. the definitive trial of triglyceride lowering among patients with type 2 diabetes mellitus and elevated triglycerides. The rates of death and MI rise incrementally with higher CAC score among patients with diabetes mellitus. these tests appear to demonstrate disease and even to predict CHD events across a population of patients. Further research is necessary to determine whether triglyceride lowering in this subpopulation 1795 . however.38). including coronary CT angiography (CCTA). prospective studies have been performed to suggest that the detection of subclinical CAD by CAC leads to improvement in clinical events. although the latter study was discontinued prematurely because of recruitment difficulties and a lower-thanexpected event rate. The neutral results of the DIAD study appeared to be buttressed by those of the Do You Need to Assess Myocardial Ischemia in Type 2 Diabetes (DYNAMIT) trial (Table 8). Future studies are necessary to more fully characterize the burden of hypoglycemia and its attendant risks. clinical trial suggests that statin therapy in asymptomatic patients with CAC . The Milan Study on Atherosclerosis and Diabetes (MiSAD) could not provide an overall estimate of myocardial perfusion defects in asymptomatic patients with diabetes mellitus because only 112 actually had stress-induced ischemic ECG changes qualifying them to proceed to myocardial perfusion imaging. Regeneron†. Janssen* None Continued on p. 1797 . Further research is necessary to best elucidate treatment recommendations on those falling outside this age range. Regeneron*. Ershow NIH Office of Dietary Supplements None None None None Johnson & Johnson† None None Judith Fradkin NIH/NIDDK None None None None None None NIH/NIDDK† Silvio E. Fox NHLBI None None None Other None None None None Sherita Hill Golden Johns Hopkins University NIH† None None None None None None Cheryl Anderson University of California at San Diego None None None None None None None George A. September 2015 can reduce CVD events in patients with type 2 diabetes mellitus. Improvements in CVD risk factors such as lowering smoking prevalence and total cholesterol and blood pressure levels have been major drivers for these improvements in CVD outcomes (236). Eckel University of Colorado Janssen† None None None None Janssen*. the incremental CVD risks associated with type 2 diabetes mellitus persist (237). Amgen* None Prakash Deedwania UCSF Fresno Program None None None None None None None Robert H. We have also summarized the current relevant CVD prevention guidelines as they pertain to type 2 diabetes mellitus. As a result. Medtronic* None None None None Bayer*. to date. 6. can reduce CVD event rates in patients with diabetes mellitus. Although these improvements also occurred in patients with type 2 diabetes mellitus. Such studies would need to be adequately powered to assess the potential of additive impact of screening results and subsequent interventions on actual patient outcomes. particularly with newer modalities that may have improved detection of functional CAD or biomarkers such as high-sensitivity troponin. AstraZeneca*. Medifast* NIH† Lora E. our goal is better primary prevention of CVD in all patients with diabetes mellitus. Imaging for subclinical CVD assessment: Although the prevalence of CAD in patients with diabetes mellitus is substantial and associated with increased morbidity and mortality. Herbalife*.S. mortality rates from CAD have been declining steadily in the U. we have highlighted key areas of controversy that require further study to allow us to make greater strides in lowering clinical CVD in this high-risk patient population. considerable work remains to be done to enhance our understanding of how to more effectively prevent CVD in patients with type 2 diabetes mellitus.1796 Scientific Statement Diabetes Care Volume 38. Sanofi† Janssen* Abby G. The purpose of this scientific statement was to update the state of the science with respect to CVD risk factor control and renal and subclinical CAD screening. the current cholesterol-lowering guidelines focus on individuals between 40 and 75 years of age. Burke University of Pittsburgh NIH† None None None None None NHLBI† Ian H. As a scientific community. SUMMARY After reaching a peak in the 1960s. Finally. Inzucchi Yale University School of Medicine Takeda† None None Pfizer*. Furthermore. Acknowledgments. Merck*. randomized trials are needed to determine whether screening for subclinical CAD. Bray Pennington Biomedical Research Center NIH† None Takeda* None None Novo-Nordisk*. Future large. Takeda* None Boehringer Ingelheim†. Novo Nordisk*. especially in an era when aggressive CVD risk factor reduction is widely endorsed for this population. it has been difficult to demonstrate that detecting disease in its preclinical or subclinical state will actually reduce event rates or improve overall patient outcomes. The authors thank Blair Underwood for her expertise in information management and referencing assistance. Disclosures Writing group disclosures Writing group member Other Speakers’ research bureau/ Expert support honoraria witness Employment Research grant Ownership interest Consultant/ advisory board Caroline S. de Boer University of Washington Abbvie†. 000 or more of the fair market value of the entity. Roche*. ZS Pharma† None Mahesh J. Eli Lilly*. Gilead*. A relationship is considered to be “modest” if it is less than “significant” under the preceding definition. or owns $10.000 or more of the fair market value of the entity.care. Glytec*.org Fox and Associates Writing group disclosures—Continued Writing group member Mikhail Kosiborod Employment Other Speakers’ research bureau/ Expert support honoraria witness Research grant Ownership interest Consultant/ advisory board Other Mid America Heart Institute Gilead†. A relationship is considered to be “modest” if it is less than “significant” under the preceding definition. which all members of the writing group are required to complete and submit. Amgen†. Edwards Lifesciences*. 1797 . ARMMS Trial† None None None SE Quality Healthcare Consulting†. or 5% or more of the person’s gross income.diabetesjournals. Regeneron*. Baylor College of Medicine Department of Veterans Affairs*. or 5% or more of the person’s gross income. Nelson National Institutes of Health None None None None None AstraZeneca†.000 or more during any 12-month period. or owns $10. †Significant. A relationship is considered to be “significant” if (a) the person receives $10. Virani Speakers’ bureau/ honoraria Expert witness Ownership interest Consultant/ advisory board Other This table represents the relationships of reviewers that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Questionnaire. which all reviewers are required to complete and submit. Eisai†. *Significant. Vafiadis None None This table represents the relationships of writing group members that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Questionnaire. Nestle*. Intuitive* None Elizabeth Selvin Johns Hopkins Bloomberg School of Public Health NIH/NIDDK† None None None None None None American Heart Association None None None None None None None Laurie Quinn Dorothea K. AstraZeneca† Gilead† None None None Robert G. American Heart Association*. Schauer Cleveland Clinic STAMPEDE Trial†. Patel Merck Research Laboratories None None None None None None Merck Research Laboratories† Michael Pignone University of North Carolina None None None None None None None University of Illinois at Chicago None None None None None None None Philip R. or (b) the person owns 5% or more of the voting stock or share of the entity. Sanofi Aventis†. SurgiQuest* Ethicon*. A relationship is considered to be “significant” if (a) the person receives $10. Takeda*. or (b) the person owns 5% or more of the voting stock or share of the entity. *Modest.000 or more during any 12-month period. GSK*. Genentech†. American Diabetes Association* None None None None None None Leigh Perrault Salim S. Reviewer disclosures Reviewer Employment Research grant Other research support William Borden George Washington University None None None None None None None Deborah Chyun New York University None None None None None None None University of Colorado None None None None None None None VA Medical Center. Lee CM. Evaluation.34:84–89 33. Ohkubo Y. Look AHEAD Research Group.. Diabetes Care 2011. et al. DESIR Study Group. Deleted in proof 8. Colagiuri S. and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Church TS. et al. Diabetes Care 2011. Day N. Liew G. the National Institute of Diabetes and Digestive and Kidney Diseases. Schriger DL. Go AS.305: 892].34:1888]. Clin Chem 2005.32:2027–2032 13. Brancati FL. Circulation 2006. Mechanick JI. Matsushita K. 1999-2010 [published correction appears in N Engl J Med 2013. Steffes MW. Circulation 2013. Meigs JB. 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